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Introduction Oxidative stress and exacerbated generation of advanced glycation end products (AGEs) participate in the onset of diabetic complications. Lycopene is a potent antioxidant; evidence accounts for its ability to mitigate diabetic disturbances, including the deleterious events of advanced glycation. Therefore, this carotenoid has emerged as a candidate to be used in combination with antidiabetic drugs, such as metformin, attempting to counteract the glycoxidative stress. This study investigated the effects of the treatments with lycopene or metformin, alone or in combination, on glycoxidative stress biomarkers and antioxidant defenses in diabetic rats. Methods Streptozotocin-induced diabetic rats were treated for 35 days with lycopene (45 mg/kg) or metformin (250 mg/kg), alone or as mixtures in yoghurt. Plasma levels of glucose, triglycerides, cholesterol, thiobarbituric acid reactive substances and protein carbonyl groups (biomarkers of oxidative damage), fluorescent AGEs (biomarkers of advanced glycation), and paraoxonase 1 activity (antioxidant enzyme) were assessed. Changes in the hepatic and renal levels of glycoxidative damage biomarkers and the activities of antioxidant enzymes were investigated. Results The combination of lycopene with metformin maintained the beneficial effects of the isolated treatments, improving the glucose tolerance and lipid profile, lessening biomarkers of oxidative damage, and increasing the paraoxonase 1 activity. Besides, the combined therapy caused further decreases in postprandial glycemia, plasma levels of cholesterol and AGEs, avoided lipid peroxidation (plasma, kidney), and increased antioxidant defenses, mainly the activity of superoxide dismutase (liver, kidney), indicating the maintenance of the lycopene effects. Conclusion Lycopene combined with metformin may act synergistically in the control of postprandial glycemia, dyslipidemia and glycoxidative stress, as well as increased antioxidant defenses, arising as a promising therapeutic strategy to mitigate diabetic complications.

Made available in DSpace on 2020-12-12T02:09:50Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-01-01 Both oxidative stress and the exacerbated generation of advanced glycation end products (AGEs) have crucial roles in the onset and progression of diabetic complications. Curcumin has antioxidant and antidiabetic properties; its combination with compounds capable of preventing the advanced glycation events, such as aminoguanidine, is an interesting therapeutic option to counteract diabetic complications. This study is aimed at investigating the effects of treatments with curcumin or aminoguanidine, alone or in combination, on metabolic alterations in streptozotocin-diabetic rats; the focus was mainly on the potential of these bioactive compounds to oppose the glycoxidative stress. Curcumin (90 mg/kg) or aminoguanidine (50 and 100 mg/kg), alone or in combination, slightly decreased glycemia and the biomarkers of early protein glycation, but markedly decreased AGE levels (biomarkers of advanced glycation) and oxidative damage biomarkers in the plasma, liver, and kidney of diabetic rats. Some novel insights about the in vivo effects of these bioactive compounds are centered on the triggering of cytoprotective machinery. The treatments with curcumin and/or aminoguanidine increased the activities of the antioxidant enzymes (paraoxonase 1, superoxide dismutase, and catalase) and the levels of AGE detoxification system components (AGE-R1 receptor and glyoxalase 1). In addition, combination therapy between curcumin and aminoguanidine effectively prevented dyslipidemia in diabetic rats. These findings demonstrate the combination of curcumin (natural antioxidant) and aminoguanidine (prototype therapeutic agent with anti-AGE activity) as a potential complementary therapeutic option for use with antihyperglycemic agents, which may aggregate beneficial effects against diabetic complications. São Paulo State University (UNESP) School of Pharmaceutical Sciences Department of Clinical Analysis Federal University of Alfenas (UNIFAL-MG) School of Pharmaceutical Sciences Department of Clinical and Toxicological Analysis Paulista University (UNIP) Institute of Health Sciences São Paulo State University (UNESP) School of Pharmaceutical Sciences Department of Clinical Analysis

Made available in DSpace on 2019-10-06T16:27:56Z (GMT). No. of bitstreams: 0 Previous issue date: 2019-08-05 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Universidade Estadual Paulista Caffeic acid (CA) is a plant metabolite acting as a carcinogenic inhibitor, and exhibits a high antioxidant effect and some antimicrobial activity. Besides, this compound can be useful in the prevention of heart diseases and atherosclerosis, among others. The present study aims to determine the in vitro antioxidant activity of CA in order to increase the frequency of its use and reliability in the prevention of damage caused by free radicals and other reactive species. The tests performed were as follows: Radical anion superoxide capture; crocin bleaching assay; capturing ability of hypochlorous acid; H 2 O 2 capture; capturing capacity of the ABTS •+ /DPPH • ; and SOD-like activity. The values of the CA antioxidant activity were very close to the values of standards in all tests. Besides, CA presented an antioxidant activity greater than that of ascorbic acid and trolox, and its advantages include higher stability than ascorbic acid and extraction from natural sources, as opposed to trolox. Department of Drugs and Medicines São Paulo State University (UNESP) School of Pharmaceutical Sciences Department of Clinical Analysis São Paulo State University (UNESP) School of Pharmaceutical Sciences Department of Drugs and Medicines São Paulo State University (UNESP) School of Pharmaceutical Sciences Department of Clinical Analysis São Paulo State University (UNESP) School of Pharmaceutical Sciences FAPESP: 2015/02619-3

Made available in DSpace on 2021-06-25T10:58:51Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-08-01 Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Aim: There is growing evidence about the ability of cyclic adenosine monophosphate (cAMP) signaling and nonselective phosphodiesterase (PDE) inhibitors on mitigate muscle atrophy. PDE4 accounts for the major cAMP hydrolyzing activity in skeletal muscles, therefore advances are necessary about the consequences of treatment with PDE4 inhibitors on protein breakdown in atrophied muscles. We postulated that rolipram (selective PDE4 inhibitor) may activate cAMP downstream effectors, inhibiting proteolytic systems in skeletal muscles of diabetic rats. Main methods: Streptozotocin-induced diabetic rats were treated with 2 mg/kg rolipram for 3 days. Changes in the levels of components belonging to the proteolytic machineries in soleus and extensor digitorum longus (EDL) muscles were investigated, as well as cAMP effectors. Key findings: Treatment of diabetic rats with rolipram decreased the levels of atrogin-1 and MuRF-1 in soleus and EDL, and reduced the activities of calpains and caspase-3; these findings partially explains the low ubiquitin conjugates levels and the decreased proteasome activity. The inhibition of muscle proteolysis may be occurring due to phosphorylation and inhibition of forkhead box O (FoxO) factors, probably as a consequence of the increased cAMP levels, followed by the activation of PKA and Akt effectors. Akt activation may be associated with the increased levels of exchange protein directly activated by cAMP (EPAC). As a result, rolipram treatment spared muscle mass in diabetic rats. Significance: The antiproteolytic responses associated with PDE4 inhibition may be helpful to motivate future investigations about the repositioning of PDE4 inhibitors for the treatment of muscle wasting conditions. São Paulo State University (Unesp) School of Pharmaceutical Sciences Department of Clinical Analysis Department of Physiology Ribeirão Preto Medical School University of São Paulo Department of Biological Sciences Federal University of Ouro Preto Departments of Biochemistry and Immunology Ribeirão Preto Medical School University of São Paulo São Paulo State University (Unesp) School of Pharmaceutical Sciences Department of Clinical Analysis CNPq: 479817/2013-8

Made available in DSpace on 2020-12-12T02:19:05Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-10-01 Universidade Estadual Paulista Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Aim: The pharmacological properties of pentoxifylline have been re-evaluated, particularly in chronic kidney disease in diabetes, favored by its anti-inflammatory action. Definitive evidences of renal outcomes are lacking, which indicates the need for investigation of novel mechanisms of action of pentoxifylline. We postulated that components associated with the metabolism of advanced glycation end products (AGEs) may be modulated by pentoxifylline, which consequently decreases the detrimental effects of obesity on kidneys. Main methods: C57BL-6J mice were fed a high-fat diet for 14 weeks and treated with 50 mg/kg pentoxifylline during the last 7 weeks. Changes in the renal levels of AGE metabolism-associated components were investigated, with particular focus on the receptor for AGEs (RAGE), its downstream components, and components related to AGE detoxification, including glyoxalase 1 (GLO 1). Key findings: Pentoxifylline reduced body weight gain, improved insulin sensitivity and glucose tolerance, downregulated biomarkers of glycoxidative stress, and enhanced plasma paraoxonase 1 activity. In the kidneys, pentoxifylline inhibited glomerular expansion, lipid deposition, reduced pro-inflammatory cytokine levels, and induced the activation of AMP-activated protein kinase. Pentoxifylline inhibited the renal accumulation of AGEs and reduced the levels of RAGE and its downstream components, and consequently mitigated oxidative stress and apoptosis. Pentoxifylline also increased the renal levels of GLO 1 and the activities of antioxidant enzymes. Urinary albumin levels were observed to be lowered, which reconfirmed the antialbuminuric effects of pentoxifylline. Significance: The novel mechanisms of action help explain the renoprotective effects of pentoxifylline and the attenuation of obesity-associated renal complications related to glycoxidative stress. São Paulo State University (Unesp) School of Pharmaceutical Sciences Department of Clinical Analysis São Paulo State University (Unesp) Araraquara School of Dentistry Department of Physiology and Pathology Paulista University (UNIP) Institute of Health Sciences São Paulo State University (Unesp) School of Pharmaceutical Sciences Department of Clinical Analysis São Paulo State University (Unesp) Araraquara School of Dentistry Department of Physiology and Pathology FAPESP: 16/23644-9 CNPq: 305936/2017-4

Insulin with natural antioxidants is emerging as a combination treatment for diabetes mellitus that attempts to exert effective glycemic control without adverse effects. The present study aimed to investigate the additive effects on metabolic disturbances, oxidative damage, and antioxidant defenses in streptozotocin-diabetic rats treated with curcumin and a reduced insulin dose. The best results were obtained in the treatment of diabetic rats with 4-U/day insulin; however, the glycemia levels in these rats were lower than those in normal rats, indicating a risk of hypoglycemia. Isolated treatments using curcumin or insulin in a reduced dose (1 U/day) decreased glycemia, dyslipidemia, and biomarkers of liver and kidney damage and increased the activity of hepatic antioxidants (superoxide dismutase and glutathione peroxidase), however, only to a lesser extent than 4-U/day insulin, without improvements in catalase activity or plasma lipid peroxidation. Decreases in glycemia, dyslipidemia, and tissue damage markers were more evident in the curcumin + 1-U/day insulin treatment than those seen in isolated treatments. The activity of hepatic antioxidants, including catalase, was further increased, and biomarkers of oxidative damage were decreased. Curcumin with a reduced insulin dose appears to be a promising strategy for combating the complications associated with diabetes and oxidative stress.

Made available in DSpace on 2018-11-26T17:54:32Z (GMT). No. of bitstreams: 0 Previous issue date: 2018-01-01 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Scientific Support and Development Program of the School of Pharmaceutical Sciences of UNESP (PADC/FCFAr, UNESP) There have been few studies on the pharmacological properties of Rhamnus sphaerosperma var. pubescens, a native Brazilian species popularly known as fruto-de-pombo. The aim of this study was to investigate the scavenging capacity of emodin, physcion, and the ethanolic crude extract of Rhamnus sphaerosperma var. pubescens against reactive oxygen and nitrogen species, as well as their role and plausible mechanisms in prompting cell death and changes in AKT phosphorylation after cervical (SiHa and C33A) and oral (HSC-3) squamous cell carcinoma treatments. Emodin was shown to be the best scavenger of NO center dot and O-2(center dot-), while all samples were equally effective in HOCl/OCl- capture. Emodin, physcion, and the ethanolic extract all exhibited cytotoxic effects on SiHa, C33A, HSC3, and HaCaT (immortalized human keratinocytes, nontumorigenic cell line), involving mixed cell death (apoptosis and necrosis) independent of the caspase activation pathway. Emodin, physcion, and the ethanolic extract increased intracellular oxidative stress and DNA damage. Emodin decreased the activation of AKT in all tumor cells, physcion in HSC3 and HaCaT cells, and the ethanolic extract in C33A and HaCaT cells, respectively. The induction of cancer cell death by emodin, physcion, and the ethanolic crude extract of Rhamnus sphaerosperma var. pubescens was related to an increase in intracellular oxidative stress and DNA damage and a decrease in AKT activation. These molecules are therefore emerging as interesting candidates for further study as novel options to treat cervical and oral carcinomas. Sao Paulo State Univ UNESP, Sch Pharmaceut Sci, Dept Clin Anal, BR-14800903 Araraquara, SP, Brazil Fed Univ Parana UFPR, Dept Pharm, BR-80210170 Curitiba, PR, Brazil Fed Univ Parana UFPR, Dept Chem, BR-80210170 Curitiba, PR, Brazil Sao Paulo State Univ UNESP, Sch Pharmaceut Sci, Dept Clin Anal, BR-14800903 Araraquara, SP, Brazil

Advances in the knowledge of the mechanisms controlling protein breakdown in skeletal muscles have allowed the exploration of new options for treating muscle-wasting conditions. Pentoxifylline (PTX), a nonselective phosphodiesterase (PDE) inhibitor, attenuates the loss of muscle mass during catabolic conditions, mainly via inhibiting protein breakdown. The aim of this study was to explore the mechanisms by which PTX inhibits proteolysis in the soleus and extensor digitorum longus (EDL) muscles of streptozotocin-induced diabetic rats. The levels of atrogin-1 and muscle RING finger-1 were decreased, as were the activities of caspase-3 (EDL) and calpains (soleus and EDL), in diabetic rats treated with PTX, which at least partly explains the drop in the ubiquitin conjugate (EDL) levels and in proteasome activity (soleus and EDL). Treatment with PTX decreased PDE activity and increased cAMP content in muscles of diabetic rats; moreover, it also increased both the protein levels of exchange protein directly activated by cAMP (EPAC, a cAMP effector) and the phosphorylation of Akt. The loss of muscle mass was practically prevented in diabetic rats treated with PTX. These findings advance our understanding of the mechanisms underlying the antiproteolytic effects of PTX and suggest the use of PDE inhibitors as a strategy to activate cAMP signaling, which is emerging as a promising target for treating muscle mass loss during atrophic conditions.NEW & NOTEWORTHY cAMP signaling has been explored as a strategy to attenuate skeletal muscle atrophies. Therefore, in addition to β2AR agonists, phosphodiesterase inhibitors such as pentoxifylline (PTX) can be an interesting option. This study advances the understanding of the mechanisms related to the antiproteolytic effects of PTX on skeletal muscles of diabetic rats, which involve the activation of both exchange protein directly activated by cAMP and Akt effectors, inhibiting the expression of atrogenes and calpain/caspase-3-proteolytic machinery.

Made available in DSpace on 2020-12-12T01:48:30Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-02-01 The development of obesity-associated complications is related to various pathogenic events including chronic inflammation, oxidative stress and generation of advanced glycation end products (AGEs). Due to their antioxidant, anti-inflammatory and antiglycation properties, trigonelline and curcumin are interesting candidates to counteract complications of obesity and diabetes mellitus. The current study aimed to investigate the effects of treatment with curcumin or trigonelline mixed into yoghurt, alone or in combination, on mice fed high-fat diet (HFD); the focus was mainly on the potential of these phytochemicals to counteract oxidative and glycative stress. Yoghurt alone improved glucose tolerance and reduced proinflammatory cytokine levels in HFD mice; however, it did not affect the antioxidant status. Trigonelline-enriched yoghurt prevented fat accumulation in adipose tissue, improved both insulin sensitivity and glucose tolerance and exerted anti-inflammatory and antiglycation activities (reduced AGEs and AGE receptor levels and increased the levels of components related to AGE detoxification) in liver and kidney of HFD mice. Curcumin-enriched yoghurt exerted anti-inflammatory and potent antioxidant properties (increased antioxidant enzyme activities and decreased lipid peroxidation) in liver and kidney of HFD mice. However, several beneficial effects were nullified when trigonelline and curcumin were administered in combination. Trigonelline and curcumin have emerged as promising complementary therapy candidates for liver and kidney complications associated with obesity. However, the administration of these phytochemicals in combination, at least in HFD mice, was not effective; inhibition of biotransformation processes and/or the reaching of toxic doses during combined treatment may be prevailing over the individual pharmacodynamic actions of these phytochemicals. São Paulo State University (Unesp) School of Pharmaceutical Sciences Department of Clinical Analysis São Paulo State University (Unesp) Araraquara School of Dentistry Department of Physiology and Pathology Paulista University (UNIP) Institute of Health Sciences São Paulo State University (Unesp) School of Pharmaceutical Sciences Department of Clinical Analysis São Paulo State University (Unesp) Araraquara School of Dentistry Department of Physiology and Pathology

Made available in DSpace on 2019-10-06T16:21:23Z (GMT). No. of bitstreams: 0 Previous issue date: 2019-06-01 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Leishmaniasis is a group of diseases caused by protozoan parasites from the genus Leishmania. There are estimated 1.3 million new cases annually with a mortality of 20,000–30,000 per year, when patients are left untreated. Current chemotherapeutic drugs available present high toxicity and low efficacy, the latter mainly due to the emergence of drug-resistant parasites, which makes discovery of novel, safe, and efficacious antileishmanial drugs mandatory. The present work reports the synthesis, characterization by ESI-MS, 1H and 13C NMR, and FTIR techniques as well as in vitro and in vivo evaluation of leishmanicidal activity of guanidines derivatives presenting lower toxicity. Among ten investigated compounds, all being guanidines containing a benzoyl, a benzyl, and a substituted phenyl moiety, LQOF-G2 (IC50-ama 5.6 μM; SI = 131.8) and LQOF-G7 (IC50-ama 7.1 μM; SI = 87.1) were the most active against L. amazonensis intracellular amastigote, showing low cytotoxicity to the host cells according to their selectivity index. The most promising compound, LQOF-G2, was further evaluated in an in vivo model and was able to decrease 60% of the parasite load in foot lesions at a dose of 0.25 mg/kg/day. Moreover, this guanidine derivative demonstrated reduced hepatotoxicity compared to other leishmanicidal compounds and did not show nephrotoxicity, as determined by the analyses of biomarkers of hepatic damage and renal function, which make this compound a potential new hit for therapy against leishmaniasis. Laboratório de Química Orgânica Fina Departamento de Química e Biologia Faculdade de Ciências e Tecnologia Universidade Estadual Paulista – UNESP, Campus de Presidente Prudente, Rua Roberto Simonsen, 305 Programa de Pós-Graduação em Ciência e Tecnologia de Materiais (POSMAT) Universidade Estadual Paulista – UNESP Departamento de Análises Clínicas Faculdade de Ciências Farmacêuticas Universidade Estadual Paulista – UNESP Campus de Araraquara, Rodovia Araraquara-Jaú km1 Department of Pharmaceutical Chemistry Faculty of Life Sciences University of Vienna, Althanstraße 14 Laboratório ThoMSon de Espectrometria de Massas Instituto de Química Universidade de Campinas – UNICAMP Departamento de Química Faculdade de Filosofia Ciências e Letras de Ribeirão Preto Universidade de São Paulo – USP, Avenida dos Bandeirantes, 3900 Department of Analytical Chemistry Faculty of Chemistry University of Vienna, Währinger Straße 38 Department of Neuroproteomics Paracelsus Medical University Laboratório de Química Orgânica Fina Departamento de Química e Biologia Faculdade de Ciências e Tecnologia Universidade Estadual Paulista – UNESP, Campus de Presidente Prudente, Rua Roberto Simonsen, 305 Programa de Pós-Graduação em Ciência e Tecnologia de Materiais (POSMAT) Universidade Estadual Paulista – UNESP Departamento de Análises Clínicas Faculdade de Ciências Farmacêuticas Universidade Estadual Paulista – UNESP Campus de Araraquara, Rodovia Araraquara-Jaú km1 FAPESP: 2013/08248-1 FAPESP: 2013/24487-6 FAPESP: 2016/19289-9 FAPESP: 2017/03552-5

Clara Maria Pinheiro-Dardis,1 Vânia Ortega Gutierres,1 Renata Pires Assis,1 Sabrina Messa Peviani,2 Gabriel Borges Delfino,2 João Luiz Quagliotti Durigan,3 Tania de Fátima Salvini,2 Amanda Martins Baviera,1 Iguatemy Lourenço Brunetti1 1São Paulo State University (UNESP), School of Pharmaceutical Sciences, Department of Clinical Analysis, Araraquara, São Paulo, Brazil; 2Federal University of São Carlos (UFSCar), Department of Physical Therapy, São Carlos, São Paulo, Brazil; 3Physical Therapy Division, University of Brasilia, Brasilia, Federal District, Brazil Background: The aim of this study was to evaluate the changes in biomarkers of skeletal muscle proteolysis (atrogin-1, muscle RING finger-1 protein [MuRF-1]) and inflammation (nuclear factor kappa-B) in skeletal muscles of rats under two catabolic conditions, diabetes mellitus (DM) and acute joint inflammation, and the effects of insulin therapy. Materials and methods: Male Wistar rats were divided into groups without diabetes – normal (N), saline (NS), or Ɩ-carrageenan (NCa) injection into the tibiotarsal joint – and groups with diabetes – diabetes (D), plus insulin (DI), saline (DS), or Ɩ-carrageenan (DCa) injection into the tibiotarsal joint, or Ɩ-carrageenan injection and treatment with insulin (DCaI). Three days after Ɩ-carrageenan injection (17 days after diabetes induction), tibialis anterior (TA) and soleus (SO) skeletal muscles were used for analysis. Results: DM alone caused a significant decrease in the mass of TA and SO muscles, even with low levels of atrogenes (atrogin-1, MuRF-1), which could be interpreted as an adaptive mechanism to spare muscle proteins under this catabolic condition. The loss of muscle mass was exacerbated when Ɩ-carrageenan was administered in the joints of diabetic rats, in association with increased expression of atrogin-1, MuRF-1, and nuclear factor kappa-B. Treatment with insulin prevented the increase in atrogin-1 (TA, SO) and the loss of muscle mass (SO) in diabetic-carrageenan rats; in comparison with TA, SO muscle was more responsive to the anabolic actions of insulin. Conclusion: Acute joint inflammation overcame the adaptive mechanism in diabetic rats to prevent excessive loss of muscle mass, worsening the catabolic state. The treatment of diabetic-carrageenan rats with insulin prevented the loss of skeletal muscle mass mainly via atrogin-1 inhibition. Under the condition of DM and inflammation, muscles with the prevalence of slow-twitch, type 1 fibers were more responsive to insulin treatment, recovering the ability to grow. Keywords: diabetes mellitus, inflammation, muscle proteolysis, atrogenes, creatine kinase, NF-κB, insulin

Leishmaniasis is a disease found throughout the (sub)tropical parts of the world caused by protozoan parasites of the Leishmania genus. Despite the numerous problems associated with existing treatments, pharmaceutical companies continue to neglect the development of better ones. The high toxicity of current drugs combined with emerging resistance makes the discovery of new therapeutic alternatives urgent. We report here the evaluation of a binuclear cyclopalladated complex containing Pd(II) and N , N ′-dimethylbenzylamine (Hdmba) against Leishmania amazonensis . The compound [Pd(dmba)(μ-N 3 )] 2 (CP2) inhibits promastigote growth (50% inhibitory concentration [IC 50 ] = 13.2 ± 0.7 μM) and decreases the proliferation of intracellular amastigotes in in vitro incubated macrophages (IC 50 = 10.2 ± 2.2 μM) without a cytotoxic effect when tested against peritoneal macrophages (50% cytotoxic concentration = 506.0 ± 10.7 μM). In addition, CP2 was also active against T. cruzi intracellular amastigotes (IC 50 = 2.3 ± 0.5 μM, selective index = 225), an indication of its potential for use in Chagas disease therapy. In vivo assays using L. amazonensis -infected BALB/c showed an 80% reduction in parasite load compared to infected and nontreated animals. Also, compared to amphotericin B treatment, CP2 did not show any side effects, which was corroborated by the analysis of plasma levels of different hepatic and renal biomarkers. Furthermore, CP2 was able to inhibit Leishmania donovani topoisomerase 1B ( Ld topo1B), a potentially important target in this parasite. (This study has been registered at ClinicalTrials.gov under identifier NCT02169141.)

Made available in DSpace on 2015-10-21T20:55:59Z (GMT). No. of bitstreams: 0 Previous issue date: 2015-01-01. Added 1 bitstream(s) on 2015-10-22T09:52:46Z : No. of bitstreams: 1 WOS000355808600001.pdf: 2624706 bytes, checksum: 0e81870c7faece906b37386dfea2c112 (MD5) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Faculdade de Ciencias Farmaceuticas (FCFAr-UNESP) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) This study measures the curcumin concentration in rat plasma by liquid chromatography and investigates the changes in the glucose tolerance and insulin sensitivity of streptozotocin-diabetic rats treated with curcumin-enriched yoghurt. The analytical method for curcumin detection was linear from 10 to 500 ng/mL. The C-max and the time to reach C-max (t(max)) of curcumin in plasma were 3.14 perpendicular to 0.9 mu g/mL and 5 minutes (10 mg/kg, i.v.) and 0.06 perpendicular to 0.01 mu g/mL and 14 minutes (500 mg/kg, p.o.). The elimination half-time was 8.64 +/- 2.31 (i.v.) and 32.70 +/- 12.92 (p.o.) minutes. The oral bioavailability was about 0.47%. Changes in the glucose tolerance and insulin sensitivity were investigated in four groups: normal and diabetic rats treated with yoghurt (NYOG and DYOG, resp.) and treated with 90 mg/kg/day curcumin incorporated in yoghurt (NC90 and DC90, resp.). After 15 days of treatment, the glucose tolerance and the insulin sensitivity were significantly improved in DC90 rats in comparison with DYOG, which can be associated with an increase in the AKT phosphorylation levels and GLUT4 translocation in skeletal muscles. These findings can explain, at least in part, the benefits of curcumin-enriched yoghurt to diabetes and substantiate evidences for the curcumin metabolite(s) as being responsible for the antidiabetic activity. Department of Biochemistry and Immunology, School of Medicine, University of São Paulo (USP), Avenida Bandeirantes 3900, 14040-900 Ribeirão Preto, SP, Brazil Department of Clinical Analysis, School of Pharmaceutical Sciences, São Paulo State University (UNESP), Rodovia Araraquara-Jaú Km 01, 14801-902 Araraquara, SP, Brazil Department of Natural Active Principles and Toxicology, School of Pharmaceutical Sciences, São Paulo State University (UNESP), Rodovia Araraquara-Jaú Km 01, 14801-902 Araraquara, SP, Brazil

Made available in DSpace on 2018-12-11T17:10:49Z (GMT). No. of bitstreams: 0 Previous issue date: 2017-04-01 Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Combination therapy using natural antioxidants to manage diabetes mellitus and its complications is an emerging trend. The aim of this study was to investigate the changes promoted by treatment of streptozotocin (STZ)-diabetic rats with yoghurt enriched with the bioactives curcumin, lycopene, or bixin (the latter two being carotenoids). Antioxidants were administered individually, or as mixtures, and biomarkers of metabolic and oxidative disturbances, particularly those associated with cardiovascular risk, were assessed. Treatment of STZ-diabetic rats with natural products individually decreased glycemia, triacylglycerol, total-cholesterol, oxidative stress biomarkers, including oxidized low-density lipoprotein (ox-LDL), and increased the activities of antioxidant enzymes. Individual carotenoids increased both high-density lipoprotein (HDL) and paraoxonase levels, whereas curcumin increased only paraoxonase. Treatments with mixtures of curcumin and lycopene or bixin had combined effects, decreasing biomarkers of carbohydrate and lipid disturbances (curcumin effect), increasing the HDL levels (carotenoids effects) and mitigating oxidative stress (curcumin and carotenoids effects). The combined effects also led to prevention of the LDL oxidation, thereby mitigating the cardiovascular risk in diabetes. These findings provide evidence for the beneficial effect of curcumin and carotenoid mixtures as a supplementation having antioxidant and antiatherogenic potentials, thus appearing as an interesting strategy to be studied as a complementary therapy for diabetic complications. Department of Clinical Analysis School of Pharmaceutical Sciences São Paulo State University-UNESP Department of Clinical Analysis School of Pharmaceutical Sciences São Paulo State University-UNESP CNPq: 141998/2012-1 FAPESP: 1998/09152-6

Made available in DSpace on 2015-11-03T15:29:43Z (GMT). No. of bitstreams: 0 Previous issue date: 2014-12-03. Added 1 bitstream(s) on 2015-11-04T10:16:09Z : No. of bitstreams: 1 WOS000349128700062.pdf: 785604 bytes, checksum: 31ca251b353eeb0ee9a7571c0e3acc8d (MD5) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Knowing that curcumin has low bioavailability when administered orally, and that piperine has bioenhancer activity by inhibition of hepatic and intestinal biotransformation processes, the aim of this study was to investigate the antidiabetic and antioxidant activities of curcumin (90 mg/kg) and piperine (20 or 40 mg/kg), alone or co-administered, incorporated in yoghurt, in streptozotocin (STZ)-diabetic rats. The treatment for 45 days of STZ-diabetic rats with curcuminenriched yoghurt improved all parameters altered in this experimental model of diabetes: the body weight was increased in association with the weight of skeletal muscles and white adipose tissues; the progressive increase in the glycemia levels was avoided, as well as in the glycosuria, urinary urea, dyslipidemia, and markers of liver (alanine and aspartate aminotransferases and alkaline phosphatase) and kidney (urinary protein) dysfunction; the hepatic oxidative stress was decreased, since the activities of the antioxidant enzymes superoxide dismutase, catalase and gluthatione peroxidase were increased, and the levels of malondialdehyde and protein carbonyl groups were reduced. The dose of 20 mg/kg piperine also showed antidiabetic and antioxidant activities. The treatment of STZ-diabetic rats with both curcumin and 20 mg/kg piperine in yoghurt did not change the antidiabetic and antioxidant activities of curcumin; notably, the treatment with both curcumin and 40 mg/kg piperine abrogated the beneficial effects of curcumin. In addition, the alanine aminotransferase levels were further increased in diabetic rats treated with curcumin and 40 mg/kg piperine in comparison with untreated diabetic rats. These findings support that the co-administration of curcumin with a bioenhancer did not bring any advantage to the curcumin effects, at least about the antidiabetic and antioxidant activities, which could be related to changes on its biotransformation. Sao Paulo State Univ UNESP, Sch Pharmaceut Sci, Dept Clin Anal, Sao Paulo, Brazil Sao Paulo State Univ UNESP, Sch Pharmaceut Sci, Dept Clin Anal, Sao Paulo, Brazil

Made available in DSpace on 2016-01-28T16:56:15Z (GMT). No. of bitstreams: 0 Previous issue date: 2014. Added 1 bitstream(s) on 2016-01-28T17:02:35Z : No. of bitstreams: 1 ISSN2231-2919-2014-04-2340-2356.pdf: 724029 bytes, checksum: 88da300f76356f9da53885c189d521a4 (MD5) Aims: The study investigated the in vivo antioxidant activity and the in vitro radical scavenging capacity of the Combretum lanceolatum Pohl (Combretaceae) flowers ethanolic extract (ClEtOH) in streptozotocin-diabetic rats. Place and Duration of Study: Department of Chemistry, Federal University of Mato Grosso, Cuiabá, Brazil; between February 2012 and December 2012. Methodology: Male Wistar rats were divided into four groups: Normal rats treated with water/vehicle (N); diabetic rats treated with water (DC); diabetic rats treated with 250 mg/kg (DT250) or with 500mg/kg (DT500) of ClEtOH. After 21 days of treatment, liver samples were used for the analysis of the oxidative stress biomarkers and activity of antioxidant enzymes. In vitro radical scavenger capacity was investigated by the following methods: DPPH radical scavenging, ABTS radical cation decolorization and crocin bleaching assays. Results: Significant oxidative stress was observed in liver of DC, since the malondialdehyde (MDA, biomarker of lipoperoxidation) levels were increased in comparison with N. Increased activities of the antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were also observed in DC, which could represent a compensatory mechanism against oxidative stress. Glutathione (GSH) levels were lower and similar between N and DC. The MDA levels were significantly decreased in liver of rats from DT250 and DT500, reaching levels similar those of N, suggesting that ClEtOH prevented lipoperoxidation. The treatment of diabetic rats with ClEtOH also increased the GSH levels, as well as increased the GSH-Px activity, and did not change the SOD activity. The results of in vitro radical scavenging capacity indicated that ClEtOH is highly active. Conclusion: These findings indicate that ClEtOH has antioxidant properties in liver of diabetic rats, decreasing lipoperoxidation and increasing the endogenous antioxidant responses. Both the antihyperglycemic effect and the capacity to scavenge free radicals may be related to the antioxidant activity of ClEtOH in diabetes. Universidade Estadual Paulista Júlio de Mesquita Filho, Departamento de Análises Clínicas, Faculdade de Ciências Farmacêuticas de Araraquara, Araraquara, Rua Expedicionários do Brasil, 1621, Centro, CEP 14801-902, SP, Brasil Universidade Estadual Paulista Júlio de Mesquita Filho, Departamento de Análises Clínicas, Faculdade de Ciências Farmacêuticas de Araraquara, Araraquara, Rua Expedicionários do Brasil, 1621, Centro, CEP 14801-902, SP, Brasil

We investigated the effects of prolonged treatment of diabetic rats with curcumin-supplemented yoghurt on the physiological and biochemical changes associated with diabetes mellitus. An established metabolic cage model was used to assess these changes in three groups of streptozotocin-diabetic rats which had been administered, by gavage, curcumin blended into yoghurt in the doses of 30, 60 and 90 mg/kg body weight (BW) per d (groups DC30, DC60, DC90) for 31 d. One group of non-diabetic rats was also treated with 90 mg/kg BW per d curcumin (NDC90). Three control groups of diabetic animals received water (DW), yoghurt (DY) and insulin at 27·78 μmol/d by subcutaneous injection (DI). Also, two groups of non-diabetic animals received water (NDW) and yoghurt (NDY). Groups DI and DC90 exhibited significant falls, relative to DW and DY, in food and water intake, urine volume, glycaemia, urinary urea and glucose, proteinuria, serum TAG and activities of aspartate and alanine aminotransferases, and higher hepatic glycogen and BW. These improvements were greater in DI than in DC90. No difference was observed in the serum levels of total cholesterol or HDL-cholesterol, or in the masses of adipose and muscular tissues, between DC90 and DW or DY. Moreover, the improvements in curcumin-treated rats, relative to DW and DY, were significant and dose-dependent. The NDC90 group also showed no difference from the NDW or NDY groups, in any of the markers for diabetes. In conclusion, curcumin mixed into yoghurt at the highest dose tested exhibited anti-diabetic activity, improving significantly most of the markers assessed in this study.

Made available in DSpace on 2015-10-21T20:55:41Z (GMT). No. of bitstreams: 0 Previous issue date: 2015-04-11. Added 1 bitstream(s) on 2015-10-22T09:52:47Z : No. of bitstreams: 1 WOS000352834800001.pdf: 707045 bytes, checksum: 40d1cdac544a1cd85a5ce03f005acd3d (MD5) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Fundação para o Desenvolvimento da UNESP (FUNDUNESP) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Background: In view of the prevalence of oxidative stress in chronic kidney disease (CKD) patients, the loss of low-molecular-weight biomolecules by hemodialysis and the antioxidant potential of some uremic solutes that accumulate in CKD, we used in vitro model systems to test the antioxidant potential of the following uremic solutes: uric acid, hippuric acid, p-cresol, phenol, methylguanidine, L-arginine, L-tyrosine, creatinine and urea.Methods: The in vitro antioxidant efficiencies of the uremic solutes, isolated or in mixtures, were tested with the following assays: i) ABTS radical cation decolorization assay; ii) hypochlorous acid (HOCl/OCl-) scavenging activity; iii) superoxide anion radical (O-2(center dot-)) scavenging activity; iv) crocin bleaching assay (capture of peroxyl radical, ROO center dot); v) hydrogen peroxide (H2O2) scavenging activity.Results: Four of the tested uremic solutes (p-cresol, phenol, L-tyrosine, uric acid) were effective antioxidants and their IC50 were found in three model systems: ABTS(center dot+), HOCl/OCl- and crocin bleaching assay. In the 4-solutes mixtures, each one of the solute captured 12.5% for the IC50 of the mixture to ABTS(center dot+) or HOCl/OCl-, exhibiting a virtually exact additive effect. In the 2-solutes mixtures, for ROO center dot capture, it was observed the need of more mass of uremic solutes to reach an IC50 value that was higher than the projected IC50, obtained from the IC50 of single solutes (25% of each, in the binary mixtures) in the same assay. Inmodel systems for O-2(center dot-) and H2O2, none of the uremic solutes showed scavenging activity.Conclusions: The use of the IC50 as an analytical tool to prepare and analyze mixtures allows the determination of their scavenging capacities and may be useful for the assessment of the antioxidant status of biological samples under conditions of altered levels of the endogenous antioxidant network and/or in the employment and monitoring of exogenous antioxidant therapy. Universidade Estadual Paulista, Departamento de Análises Clínicas, Faculdade de Ciências Farmacêuticas de Araraquara Universidade Estadual Paulista, Departamento de Bioquímica e Tecnologia, Instituto de Química de Araraquara